Physical exercise protects many brain regions during normal, healthy aging and is protective in neurodegenerative diseases such as Alzheimer disease and Parkinson disease. However, the effect of exercise on retina was unknown until we recently published exciting data demonstrating that modest treadmill running protects mice from light-induced retinal degeneration (LIRD) and is protective in the rd10 mouse model of retinitis pigmentosa. Here we propose to explore this response using induced and inherited models of retina degeneration. We hypothesize that exercise has protective effects on visual outcomes in disease and during aging through biological and molecular mechanisms that are similar to those observed in the brain in response to exercise. This will be tested in a straightforward research design via two aims: In Aim 1, we will optimize exercise regimens for greatest protection. Young (3 month old) and old (12- 18 months old) mice will be run on treadmills with varying duration, speed, and intermittency. Retinal degeneration will be induced by damage (e.g., LIRD) or by genetic lesions (e.g., the Tvrm4 mouse model of retinitis pigmentosa, in replacement of rd10 mice). These experiments will guide our choice of exercise regimen in exploring the mechanisms underlying neuroprotection. In Aim 2, we will test whether exercise-induced retinal protection is meditated by effects on retinal inflammation pathways and energy homeostasis. Our initial findings support a role for brain-derived neurotrophic factor (BDNF) and suppression of reactive gliosis. We will further examine retinal neurotrophic pathways and we will explore the effect of exercise on retinal cytokine pathways and mitochondrial health and biogenesis. Finally, we will test whether exercise is protective in aged mice that exhibit a hyper-inflammatory response to injury and degeneration. Exercise is simple, inexpensive, and accessible to many people. It has known additional benefits to non-visual diseases. It should translate quickly to the clinic. Our experiments will change our fundamental understanding of the relationship of the retina to the rest of the body, just as similar exercise studies are expanding our understanding of the effects of whole-body physiology on neurodegenerative disease, aging, depression, and cognition.